To date, a variety of beta-lactam drugs have been developed and beta-lactam drugs have become clinically extremely important antimicrobial drugs. However, there are increasing number of bacterial types which have obtained resistance against beta-lactam drugs by producing beta-lactamase, which degrade beta-lactam drugs.
According to the Ambler molecular classification, beta-lactamases are largely classified into four classes. Specifically, these are Class A (TEM type, SHV type, CTX-M type and the like), Class B (IMP type, VIM type, L-1 type and the like), Class C (AmpC type) and Class D (OXA type and the like). Amongst these, Classes A, C and D types are largely classified into serine-beta-lactamase, on the other hand, Class B type is classified into metallo-beta-lactamase. It has been known that both have respectively different mechanisms to each other in terms of hydrolysis of beta-lactam drugs.
Recently, clinical problem has been occurring due to the existence of Gram negative bacteria which have become highly resistant to a number of beta-lactam drugs including Cephems and Carbapenems by producing Class A (ESBL) and D types serine-beta-lactamases which have an extended substrate spectrum, and Class B type metallo-beta-lactamase which have an extended substrate spectrum. Particularly, metallo-beta-lactamase is known to be one of the causes of obtaining multidrug-resistance in Gram negative bacteria. Cephem compounds which exhibit intermediate activity against metallo-beta-lactamase producing Gram negative bacteria are known (e.g., Patent Document 1 and Non-Patent Document 1). However, there is a demand for development of Cephem compounds which exhibit more potent antimicrobial activity, in particular more effective against a variety of beta-lactamase producing Gram negative bacteria.
One of the known antimicrobials having high anti-Gram negative bactericidal activity is Cephem compounds having a catechol group intramolecularly (e.g., Non-patent Documents 2-4). The action thereof is that the catechol group forms a chelate with Fe3+, thereby the compound is efficiently incorporated into the bacterial body through the Fe3+ transportation system on the cellular membrane (tonB-dependent iron transport system). Therefore, research has been conducted on compounds having catechol or similar structure thereto, on the 3-side chain or 7-side chain moiety on the Cephem backbone.
Patent Documents 2-8 and Non-patent Document 5 describe compounds having a partial structure of the 7-side chain and a quaternary salt structure on the Cephem backbone. However, these documents merely describe a pyridinium structure, and merely disclose compounds having a formamide group at the 7-position in most cases. Furthermore, for example, most compounds disclosed in Patent Document 2 have a penicillin structure.
Non-patent document 1 and Patent Documents 8-12 and 15 describe catechol type derivatives having a catechol group on the 3-side chain moiety on the Cephem backbone. Patent Documents 10, 11, 13 and 14 describe pseudo-catechol type derivatives having a hydroxypyridone group on the 3-side chain moiety on the Cephem backbone. Patent Documents 16 and 17 disclose Cephem compounds having a quaternary ammonium group, but do not describe a catechol type derivative.
Moreover, in the above documents, which describe Cephem compounds having a catechol group in their structure, there is no description of Class B type metallo-beta-lactamase, and specific antimicrobial activity against a wide variety of Gram negative bacteria including Class B type.
On the other hand, the present applicant filed an application of Cephem compounds having catechol type substituents (International Patent Application PCT/JP2009/068400). Furthermore, the present applicant has already filed an application relating to Cephem antimicrobial agent having potent antimicrobial activity against beta-lactamase producing Gram negative bacteria (Japanese Patent Application Ser. Nos. 2010-087130 and 2010-087131).